1. Field of the Invention
The present invention relates to the growth factor pleiotrophin, receptors for pleiotrophin, and fragments of these proteins, as well as nucleic acid sequences that encodes these proteins and protein fragments and antibodies reactive thereto. In particular, the invention relates to compositions and methods related to pleiotrophin and pleiotrophin receptor protein interactions for the treatment, prevention and detection of cell proliferation, vascular, neurological and developmental disorders, and also for the development of new compounds and methods therefor.
2. Description of the Background
Tumors of glial origin, including astrocytomas, oligodendrogliomas and ependymomas, account for almost eighty percent of all primary brain malignancies. Glioblastoma multiforme is both the single most common glial tumor and the most lethal, with a mean survival of only one year despite aggressive treatment (Holland, 2000). While these tumors exhibit multiple genetic alterations, including loss or mutation of the tumor suppressors PTEN (Wang et al., 1997), p53(Albertoni et al., 1998) and INK4a-ARF (James et al., 1996), receptor tyrosine kinase (RTK) signaling seems to play a particularly important role in tumor development and growth. During the development of tumors, a continuos interaction between the malignantly transformed cancer cells and the surrounding stromal cells takes place (Hanahan and Weinberg, 2000). During this cross-talk cancer cells induce other epithelial cells, immune cells, fibroblasts, endothelial cells, etc. to enhance the production of growth factors that will sustain the development of the tumor or, alternatively, to stop producing inhibitory factors that would impede further cancer cell expansion.
Along these lines, tumor cells will secrete growth factors that sustain their own growth by autocrine mechanisms and/or promote the growth of surrounding supportive cells and reduce their inhibitory signals by paracrine mechanisms. Glioblastomas and glioblastoma cell lines have been shown to overexpress the tyrosine kinase receptors for epidermal growth factor (EGF) (Nishikawa 1994), platelet-derived growth factor (PDGF) (Nister et al., 1991), hepatocyte growth factor (HGF) (Bowers et al., 2000), nerve growth factor (NGF) (Singer et al., 1999) and vascular endothelial growth factor (VEGF) (Holland et al., 2000). In addition, these tumors frequently overexpress the ligands for these RTKs, indicating a potential role for autocrine RTK signaling in glioblastoma growth. The importance of RTK signaling is also supported by the finding that the combined activation of two downstream targets of RTK signaling, Ras and Akt, in neural progenitor cells induces glioblastoma-like tumors in mice (Holland et al., 2000).